Non-Mendelian Genetics Study Notes

Classic Mendelian Genetics

  • Two postulates are the basic principles of gene transmission:

    • Genes are present on homologous chromosomes.

    • Chromosomes segregate and assort independently.

    • Predicting phenotypes can be tricky due to interactions of different genetic factors.

But This Isn’t the Entire Picture…

  • Dominance/recessiveness are NOT the only rules of inheritance.

  • Genes affect phenotype in multiple ways including but not limited to:

    • Mutation: The ultimate source of alleles.

    • New phenotypes can result from:

      • Eliminating enzyme function.

      • Changing relative enzyme efficiency.

      • Changing overall enzyme function.

  • Consequently, the type of mutation/allele affects the resulting phenotype significantly.

Mutation Types – Phenotype Level

  • Loss-of-function mutations:

    • Cause a loss of wild-type function.

  • Gain-of-function mutations:

    • Enhance function of the wild type.

    • Result in an increase in the quantity of gene product.

  • Neutral mutations:

    • Result in no change to the phenotype.

    • Have no selective advantage or disadvantage affecting evolutionary fitness.

Loss-of-Function Mutations

  • Also referred to as “inactivating mutations.”

  • Result in the gene being partially or fully inactive.

  • Typically, these mutations are recessive, although this is not an absolute rule.

    • If the loss of function is complete, it results in a null allele.

Gain-of-Function Mutations

  • Known as “activating mutations.”

  • Cause an enhancement of gene activation or its product.

  • These mutations are generally dominant in effect.

Dominant-Negative Mutations

  • Referred to as “antimorphic mutations.”

  • The mutant allele functions antagonistically to the wild-type allele.

  • Many dominant-negative mutations in humans are implicated in cancer.

Dominant-Negative Example

  • STAT3 Dominant-Negative Disease:

    • Encodes a regulatory protein that is crucial for the immune response.

    • In heterozygotes carrying the mutant allele, the mutant protein inhibits the activity of the wild-type protein due to dimerization.

  • Clinical manifestations:

    • Immune-related: Recurring Staphylococcus aureus skin boils and severe pneumonia; complications like pulmonary pneumatoceles and bronchiectasis.

    • Skin: Eczematoid dermatitis, often starting in infancy.

    • Connective Tissue/Skeletal: Characteristic facial features, scoliosis, hyperextendable joints, bone fractures, retained primary teeth.

    • Vascular/Other: Vascular tortuosity, aneurysms, gastrointestinal perforation, and elevated cancer risks (e.g., lymphoma).

Neutral Mutations

  • Do not exhibit any selective benefit or negative effect.

  • Often cannot be “seen” phenotypically.

  • Silent mutations serve as a clear example.

What Happens When Neither Allele is Dominant?

  • This scenario often leads to incomplete or partial dominance, where an intermediate phenotype emerges, signifying neither allele is dominant.

Incomplete Dominance

  • Example in Snapdragon Flowers:

    • Cross of red snapdragon (R) with white snapdragon (W) yields F1 offspring with pink flowers (RW).

    • The F2 generation manifests in a phenotypic ratio of 1/4 red (RR), 1/2 pink (RW), 1/4 white (WW).

    • Each genotype correlates with distinct phenotypes.

Incomplete Dominance—Humans

  • Tay-Sachs disease: A human biochemical disorder influenced by incomplete dominance.

    • Homozygous recessives are affected by a severe lipid-storage disorder where Hexosaminidase A activity is absent.

    • Enzyme's absence disrupts lipid metabolism.

    • Normal heterozygotes possess one copy of the mutant gene, resulting in 50% enzyme activity when compared with wild-type homozygous individuals.

Example Question (Incomplete Dominance)

  • In a plant where allele B creates blue flowers and allele b produces white flowers, with incomplete dominance (where Bb is light blue), the offspring ratio expected from a cross between a blue-flowered plant (BB) and a white-flowered plant (bb) is All light blue.

Codominance

  • Definition of Codominance:

    • Codominance refers to a situation where two alleles of a single gene produce two distinct gene products - both phenotypes are expressed.

    • Both alleles are jointly expressed within heterozygotes, indicating the absence (none) of dominance or recessiveness.

Codominance—Human Example

  • MN Blood Group in Humans:

    • Characterized by antigen glycoproteins found on red blood cell surfaces.

    • Contains two forms of glycoprotein, designated as M and N.

    • An individual can exhibit one, the other, or both.

MN Blood Group Genotype vs. Phenotype

  • Genotypes and corresponding Phenotypes:

    • M → Type M

    • MN → Type MN

    • N → Type N

  • Mating between two heterozygous MN individuals can lead to offspring expressing all three blood types due to codominant inheritance.

What if There are More Than Two Alleles?

  • Multiple Alleles:

    • The presence of three or more alleles for the same gene results in unique modes of inheritance.

Multiple Alleles—Human Example

  • Human ABO Blood Groups:

    • Serve as an example of multiple alleles influencing phenotypes.

    • Responsible alleles include:

    • IA: Produces A antigens.

    • IB: Produces B antigens.

    • i: Does not produce any antigens.

  • Interactions among these alleles dictate ABO phenotypes.

The Rules of ABO Blood Groups

  • The three alleles are:

    • IA allele

    • IB allele

    • i allele

  • Relationships:

    • IA and IB alleles are dominant to the i allele.

    • IA and IB alleles are codominant to each other.

Example Question (Blood Types)

  • If a mother has type A blood and her son has type O blood, the possible blood types of her son’s father could be:

    • D. Type A, B, or O.

    • Reasoning: For the son to exhibit type O blood, he must inherit an i allele from each parent. Therefore, the father must carry an i allele.

Lethal Alleles of Essential Genes

  • Essential Genes:

    • Critical for survival; mutations may be tolerated if the organism is heterozygous.

    • A homozygous recessive organism will not survive, as the loss of the gene's function jeopardizes viability or fitness.

    • DNA polymerase is an essential gene

Lethal Alleles: 2 Types

  • Recessive lethal alleles:

    • Result in the death of homozygous recessive individuals.

  • Dominant lethal alleles:

    • Presence of just one copy leads to death.

    • Example: Huntington disease.

Huntington’s Disease

  • Caused by a dominant autosomal allele H.

  • CAG repeats: mutational hotspot. This leads to neurodegeneration and progressive motor dysfunction in individuals carrying the allele.

  • Disease onset is delayed until adulthood.

  • Progressively characterized by

    • Neurodegeneration,

    • Dementia, and

    • Early death.

  • Raises the question of how such an allele remains prevalent in the population despite its detrimental effects.

Homozygous Lethal Alleles

  • Some homozygous lethal alleles result in distinct mutant phenotypes.

  • Example: Mutation in mice leading to yellow coat color; differs from normal agouti coat color.

  • Homozygous yellow coats are lethal in mice, resulting in death before birth.

Allelic Interactions

  • Agouti (fancy word for brown) gene in mice (coat color):

  • Alleles:

    • A (Agouti allele)

    • AY (Mutant yellow allele)

  • The AY allele acts dominantly over A to influence coat color but behaves as a homozygous recessive lethal allele.

    • The genotype AyAy does not survive.

Another Example

  • Manx Cat Inheritance Pattern: shortening tail is caused by a dominant mutation, resulting in varying tail lengths among offspring, with some being completely tailless.

  • recessive lethal example:

    • Cross involves a Manx cat (Mm) with another Manx cat (Mm). Offspring ratios are as follows:

    • MM: Early embryonic death.

    • Mm: Manx cats (1:2 ratio).

    • mm: Non-Manx (1/3).

Drosophila Balancer Chromosomes

  • Maintaining a stock of flies with a harmful mutation can be achieved through a balanced system.

  • Two different lethal or sterile mutations on homologous chromosomes (e.g., hb[1] and DI[1]) ensure that only progeny heterozygous for both mutations survive, allowing both mutations to be maintained.

    • The “+” symbol signifies a wild-type gene.

    • put a line when showing a diploid

Example Scenario (Mice)

  • In a study of short-tail allele dominance over long-tail in mice, a cross between two heterozygous short-tail mice results in a 2/3 short-tailed and 1/3 long-tailed offspring ratio, suggesting:

    • B. There is a recessive lethal allele.

    • A 2:1 ratio indicates an absent phenotypic class resulting from homozygous recessive lethality.

    • Therefore, we can represent alleles as:

    • Long-tailed = tt,

    • Short-tailed = Tt,

    • Lethal = TT (not observed).

Hypothetical Scenario (Tulips)

  • In a tulip species, with alleles producing red (R), purple (P), and white (W) colors, with R being dominant over P and W, and P dominant over W, determine the phenotype ratios for a given cross:

    • Expected ratios derived from specific crosses need to be delineated based on Mendelian genetics principles.

    • ½ red ½ purple

Genetic Probability Scenario

  • Suppose Mark, a genetic male, has a father with a rare, X-linked recessive color blindness and a non-carrier mother with cystic fibrosis, also a recessive condition.

    • Questions:

    • a) What is the probability that Mark has color blindness AND cystic fibrosis?

    • b) Mark’s sister, Markerena, is a genetic female. What is the probability that she has cystic fibrosis and is a carrier for color blindness?

    • Assessment will require understanding of inheritance patterns for X-linked and autosomal recessive traits.